Double Cord Blood Transplantation in Hematologic Malignancy

Purpose: Cord blood transplantation (CBT) is a promising alternative means of allogeneic stem cell transplantation. However, the limited cell dose of single umbilical cord blood (UCB) unit has been a major barrier to its more widespread use. With the hypothesis that double CBT (dCBT) could circumvent the cell dose problem, we analyzed the early engraftment kinetics in 10 hematologic malignancy patients given 2 partially matched dCBT.

Methods: Patients were eligible for dCBT when a single 4-6/6 HLAmatched UCB unit with adequate nucleated cell dose is unavailable. From November 2005 to June 2008, 10 patients (3 male and 7 female) with a median age of 22 years (range 10–37) and a median weight of 55kg (range 31–70 kg) were recruited, including 4 ALL, 3 AML, and 3 CML. All patients received myeloablative conditioning (Flu/Cy/TBI for 6 patients, BU/CY₂ for 2 and BU/CY₂/BCNU for one). Graft versus host disease (GVHD) prophylaxis was CSA+MMF. They received two units with at least one 5/6 HLA-match unit. The median combined graft nucleated cell (NC) dose was 3.98°Á10⁷/kg (range 3.51–7.70°Á10⁷ NC/kg), and the median CD34+ cell dose was 2.37°Á10⁵/Kg (range, 0.94–5.23°Á10⁵/kg).

Results: Eight patients (80%) had sustained hematopoietiec recovery. The median time to an absolute neutrophils count > 500 was 18 days (14'C29) and the median time to a platelet count > 20,000 was 34 days (27–46). Among those patients, one displayed the engraftment derived from both donors for six months until her death. The both units were 6/6 HLA matched the recipient, and had similar number of nucleated cells, CD34⁺ cells and CD3+ cells. The sustained hematopoiesis was derived from a single dominant one in the remianing 7 pateints. By STR-PCR, the median values of the percentage of the dominant unit was 80%(30–100%)at post-transplantatiom day 7, and they all achieve complete donor chimerism at day 28. The median infused cell dose of the predominating unit was 2.6°Á10⁷ NC/Kg (range 1.3–4.45 °Á10⁷/kg), 1.56°Á10⁵ CD34⁺/Kg, (range 0.47–4.00°Á10⁵/kg), and 0.53°Á10⁷CD3⁺/Kg (range 0.34–2.59°Á10⁷/kg), in contrast to 1.46°Á10⁷ NC/Kg (range 0.96–6.09°Á10⁷/kg), 0.87°Á10⁵CD34⁺/Kg (range 0.20–2.55°Á10⁵/kg), and 0.52°Á10⁷CD3⁺/Kg (range 0.12–1.69°Á10⁷/kg) in the nonsustained unit. When analyzed separately, units with high numbers of total nucleated cells, CD34⁺ cells or CD3⁺ cells dominate the engraftments in 4 partially overlapping patients. Only 3 of the 7 patients with donor engraftment received 2 UCB units with different degrees of HLA disparity. Of these, the better HLA-matched unit to the recipient predominated in 1 patients, while lesser matched units engrafted over the better matched units in 2 patients. Acute GVHD grade = 1 \* ROMAN ICIII was scored in 3 patients (37.5%) (1 grade = 1 \* ROMAN I, 1 grade II and 1 grade III). No patients presented acute GVHD grade IV. Three patients died (2 fungal infection, 1 serious hepatitis).

Conclusions: Two units CBT is a safe and effective alternative option for hematologic malignancy treatment. Generally, hematopoiesis will be dominated by only one unit in patient received dCBT and it may occur as early as 7days after transplantation. However, the mechanism to determine this dominancy remains elusive, as nucleated cell dose, CD34⁺ cell dose, CD3⁺ graft cell dose and HLA match all failed to predict the predominant unit.

Table 1 Characteistics of dominant and non-dominant cord blood units